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Aims: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all‐cause mortality associated with domperidone exposure in PD. Methods: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987–2011). The first recorded PD diagnosis defined index date. Time‐dependent Cox proportional hazards models estimated hazard ratios (HRs) of all‐cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti‐Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non‐PD patients. Results: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two‐fold increase in all‐cause mortality (HRadj = 2.00, 95% confidence interval [CI]: 1.64–2.45), as compared to patients never exposed to domperidone. All‐cause mortality risk was highest in those starting domperidone in the previous month [HRadj = 2.97, 95% CI: 2.06–4.27]. When compared to matched non‐PD patients, PD was associated with a 43% increased risk of all‐cause mortality, yet this increased to a 2.4‐fold increased risk among PD patients currently using domperidone. Conclusion: Current use of domperidone was associated with a two‐fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone. [ABSTRACT FROM AUTHOR]